Persistent repression of tau in the brain using engineered zinc finger protein transcription factors

Inhibition of endogenous tau improves behaviors and protects neurons from toxicity in APP/PS1 mice.

“Furthermore, inhibition of endogenous tau improves behaviors and protects neurons from toxicity in APP/PS1 mice, a mouse model with AD-like Aβ pathology [31].”

Soluble oligomeric tau may play a more essential role in neurodegeneration than insoluble fibrillar tau, including NFTs.

“These findings indicate that soluble oligomeric tau may play a more essential role in neurodegeneration than insoluble fibrillar tau (including NFT), the “tau we can see”.”

Reduction of tau mRNA using zinc finger gene therapy in mice with wild-type endogenous tau improves behavior and morphological indices of neuronal damage in context of Aβ deposits.

“Finally, reduction of tau mRNA using zinc finger gene therapy approaches (in mice with wild-type endogenous levels of tau) leads to improvements in behavior and morphological indices of neuronal damage in the context of Aβ deposits (25), consistent with the idea that soluble rather than insoluble species lead to the neuronal phenotype.”

Resolution of soluble forms of tau is sufficient to normalize morphology of dystrophic neurites around plaques.

“Another example of tau-related lesions, the dystrophic neurites around plaques, also implicates the role of soluble rather than fibrillar species since the resolution of soluble forms of tau is sufficient to lead to normalization of the morphology (25, 53).”

In preclinical models, decreasing tau protein levels via ASO strategies and recently by engineered zinc-finger transcription factors was shown to be durable and to reverse tau pathology.

“In fact, in preclinical models, decreasing tau protein levels via ASO strategies185,186 and recently by engineered zinc-finger transcription factors187 was shown to be durable and to reverse tau pathology.”